Chemical formula: C₇₁₄H₁₁₆₇N₁₉₁O₂₂₁S₆
Metreleptin mimics the physiological effects of leptin by binding to and activating the human leptin receptor, which belongs to the Class I cytokine family of receptors that signals through the JAK/STAT transduction pathway.
Only the metabolic effects of metreleptin have been studied. No effects on the distribution of subcutaneous fat are expected.
There are limited data on the pharmacokinetics of metreleptin in patients with lipodystrophy and therefore no formal exposure-response analysis has been performed.
Peak serum leptin (endogenous leptin and metreleptin) concentration (Cmax) occurred approximately 4.0 hours after subcutaneous administration of single doses ranging from 0.1 to 0.3 mg/kg in healthy adult subjects. In a supportive trial in LD patients, the median Tmax was 4 hours (range: 2 to 6 hours; N=5) following single-dose administration of metreleptin.
In studies of healthy adult subjects, following intravenous administration of metreleptin, leptin volume of distribution (endogenous leptin and metreleptin) was approximately 4 to 5 times plasma volume; volumes (mean ± SD) were 370 ± 184 mL/kg, 398 ± 92 mL/kg, and 463 ± 116 mL/kg for 0.3, 1.0, and 3.0 mg/kg/day doses, respectively.
No formal metabolism studies have been conducted.
Non-clinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Following single subcutaneous doses of 0.01 to 0.3 mg/kg metreleptin in healthy adult subjects, the half-life was 3.8 to 4.7 hours. After IV administration, metreleptin clearance was shown to be 79.6 mL/kg/h in healthy volunteers. The clearance of metreleptin appears to be delayed in the presence of ADAs. A higher accumulation is observed with higher ADA levels. Dose adjustments should be made based on clinical response.
No formal pharmacokinetic studies were conducted in patients with hepatic impairment.
No formal pharmacokinetic studies were conducted in patients with renal impairment. Non-clinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Hence, the pharmacokinetics may be altered in patients with renal impairment.
Specific clinical studies have not been conducted to assess the effect of age, gender, race, or body mass index on the pharmacokinetics of metreleptin in patients with lipodystrophy.
Non-clinical data based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity reveal no risks additional to those attributed to an excess of the expected pharmacodynamic responses, such as loss of appetite and body weight.
Two-year carcinogenicity studies in rodents have not been conducted. Metreleptin exhibits no genotoxic potential and no proliferative or preneoplastic lesions were observed in mice or dogs following treatment up to 6 months. Reproductive toxicity studies conducted in mice have revealed no adverse effects on mating, fertility or embryo-foetal development up to the maximum tested dose, approximately, 15-fold the maximum recommended clinical dose, based on body surface area of a 60 kg patient.
In a pre- and postnatal development study in mice, metreleptin caused prolonged gestation and dystocia at all tested doses, starting at, approximately, a dose identical to the maximum recommended clinical dose, based on body surface area of a 60 kg patient. Prolonged gestation resulted in the death of some females during parturition and lower survival of offspring within the immediate postnatal period. These findings are considered to be related indirectly to metreleptin pharmacology, resulting in nutritional deprivation of treated animals, and also possibly, due to an inhibitory effect on spontaneous and oxytocin-induced contractions, as has been observed in strips of human myometrium exposed to leptin. Decreased maternal body weight was observed from gestation throughout lactation at all doses and resulted in reduced weight of offspring at birth, which persisted into adulthood. However, no developmental abnormalities were observed and reproductive performance of the first or second generations was not affected at any dose.
Reproductive toxicity studies have not included toxicokinetics analysis. However, separate studies revealed that exposure of the mouse foetus to metreleptin was low (<1%) after subcutaneous administration of metreleptin to pregnant mice. The AUC exposure of pregnant mice was approximately 2 to 3 times greater than observed in non-pregnant mice after 10 mg/kg subcutaneous administration of metreleptin. A 4 to 5-fold increase in the t1/2 values was also observed in pregnant mice compared to non-pregnant mice. The greater metreleptin exposure and longer t1/2 observed in the pregnant animals may be related to a reduced elimination capacity by binding to soluble leptin receptor found at higher levels in pregnant mice.
No studies with direct administration of metreleptin to juvenile animals have been conducted. However, in published studies, leptin treatment of euleptinaemic prepubertal female mice has led to an earlier onset of puberty.
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